Fatty Acid Synthase Inhibition Activates AMP-Activated Protein Kinase in SKOV3 Human Ovarian Cancer Cells

Zhou, Weibo; Han, Wan Fang; Landree, Leslie E.; Thupari, Jagan N.; Pinn, Michael L.; Bililign, Tsion; Kim, Eun Kyoung; Vadlamudi, Aravinda; Medghalchi, Susan M.; Meskini, Rajaâ El; Ronnett, Gabriele V.; Townsend, Craig A.; Kuhajda, Francis P.

doi:10.1158/0008-5472.can-06-3439

Cited by 212 publications

(225 citation statements)

References 61 publications

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“…[20][21][22][23] The cell cycle arrest that follows FASN blockage is associated with increased levels of p21 and p53 in colon, breast, gastrointestinal, and human melanoma tumor cells. 22,[41][42][43] Indeed, ongoing experiments from our laboratory have shown that cerulenin or orlistat significantly increase p21 protein amount in B16-F10 cell lysates.…”

Section: Discussionmentioning

confidence: 99%

“…4,5 Conversely, the overexpression of FASN in several human malignancies, such as those of prostate, breast, ovary, melanoma, and soft tissue sarcomas [6][7][8][9][10][11][12][13][14][15][16][17][18][19] has been associated with poor prognosis. FASN inhibition reduces cell proliferation by blocking DNA replication during S-phase, induces apoptosis, [20][21][22][23] and decrease the size of prostate, ovarian, and breast cancer xenografts. 7,8,24 Moreover, the inhibition of FASN activity is chemopreventive in the neu-N mouse model for breast cancer.…”

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confidence: 99%

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Inhibition of fatty acid synthase in melanoma cells activates the intrinsic pathway of apoptosis

Zecchin

Rossato

Raposo

et al. 2011

Laboratory Investigation

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Fatty acid synthase (FASN) is the metabolic enzyme responsible for the endogenous synthesis of the saturated long-chain fatty acid, palmitate. In contrast to most normal cells, FASN is overexpressed in a variety of human cancers, including cutaneous melanoma, in which its levels of expression are associated with tumor invasion and poor prognosis. We have previously shown that FASN inhibition with orlistat significantly reduces the number of spontaneous mediastinal lymph node metastases following the implantation of B16-F10 mouse melanoma cells in the peritoneal cavity of C57BL/6 mice. In this study, we investigate the biological mechanisms responsible for the FASN inhibition-induced apoptosis in B16-F10 cells. Both FASN inhibitors, cerulenin and orlistat, significantly reduced melanoma cell proliferation and activated the intrinsic pathway of apoptosis, as demonstrated by the cytochrome c release and caspase-9 and -3 activation. Further, apoptosis was preceded by an increase in both reactive oxygen species production and cytosolic calcium concentrations and independent of p53 activation and mitochondrial permeability transition. Taken together, these findings demonstrate the mitochondrial involvement in FASN inhibition-induced apoptosis in melanoma cells.

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Inhibition of fatty acid synthase in melanoma cells activates the intrinsic pathway of apoptosis

Zecchin

Rossato

Raposo

et al. 2011

Laboratory Investigation

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“…36,43 Surprisingly, the pharmacological inhibition of FAS in human ovarian cancer cells led to a rapid activation of AMPK within minutes, followed by the induction of substantial cytotoxicity. 44 Blocking AMPK activation with compound C, an AMPK inhibitor, substantially abrogated the cytotoxic effect of FAS inhibition. Thus, it seems that AMPK activation plays a substantial role in the mechanism, whereby FAS inhibition induces cytotoxicity.…”

Section: Selective Ampk Activationmentioning

confidence: 99%

AMP-activated protein kinase and human cancer: cancer metabolism revisited

Kuhajda

2008

Int J Obes

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AMP-activated protein kinase (AMPK) and its upstream kinase, LKB1, act to both monitor and restore cellular energy in response to energy depletion. Studied extensively in liver and skeletal muscle, AMPK is phosphorylated and activated by LKB1 in response to increasing AMP/ATP ratios, which occur in a variety of settings including hypoxia, nutrient starvation and redox imbalance. Interest in the roles of both AMPK and LKB1 in cancer has grown substantially, following the identification of LKB1 as the tumor suppressor gene mutated in the Peutz-Jegher familial cancer syndrome. Patients with the Peutz-Jegher syndrome harbor a single inactive LKB1 gene, and acquisition of a second inactivating lesion (loss of heterozygosity) leads to the development of the cancer in a variety of organs. Thus, the loss of AMPK activation is hypothesized to promote the development of malignancy. Conversely, pharmacological AMPK activation has recently been shown to be cytotoxic to many established human cancer cell lines in vitro and in human cancer xenograft and mouse cancer allografts. Previously, changes in cell metabolism that accompanied the malignant phenotype have largely been considered a consequence of cellular transformation. Now, AMPK and energy metabolism are linked to the development and maintenance of the malignant phenotype. These findings have led to renewed interest in AMPK and cancer cell metabolism in general as potential targets for cancer therapy.

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“…Although FAS inhibition can lead to a block in the cell cycle before G 1 , there are data that support an S-phase arrest in breast cancer cells (Zhou et al, 2003) and in colon carcinoma cells ). In the current study, we demonstrated a marked, dose-dependent S-phase block at 24 h after treatment.…”

Section: Hindiii (557)mentioning

confidence: 99%

Fatty acid synthase: a novel target for antiglioma therapy

et al. 2006

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High levels of fatty acid synthase (FAS) expression have been observed in several cancers, including breast, prostate, colon and lung carcinoma, compared with their respective normal tissue. We present data that show high levels of FAS protein in human and rat glioma cell lines and human glioma tissue samples, as compared to normal rat astrocytes and normal human brain. Incubating glioma cells with the FAS inhibitor cerulenin decreased endogenous fatty acid synthesis by approximately 50%. Cell cycle analysis demonstrated a time-and dose-dependent increase in S-phase cell arrest following cerulenin treatment for 24 h. Further, treatment with cerulenin resulted in time-and dose-dependent decreases in glioma cell viability, as well as reduced clonogenic survival. Increased apoptotic cell death and PARP cleavage were observed in U251 and SNB-19 cells treated with cerulenin, which was independent of the death receptor pathway. Overexpressing Bcl-2 inhibited cerulenin-mediated cell death. In contrast, primary rat astrocytes appeared unaffected. Finally, RNAi-mediated knockdown of FAS leading to reduced FAS enzymatic activity was associated with decreased glioma cell viability. These findings suggest that FAS might be a novel target for antiglioma therapy.

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Fatty Acid Synthase Inhibition Activates AMP-Activated Protein Kinase in SKOV3 Human Ovarian Cancer Cells

Cited by 212 publications

References 61 publications

Inhibition of fatty acid synthase in melanoma cells activates the intrinsic pathway of apoptosis

Inhibition of fatty acid synthase in melanoma cells activates the intrinsic pathway of apoptosis

AMP-activated protein kinase and human cancer: cancer metabolism revisited

Fatty acid synthase: a novel target for antiglioma therapy

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